New space-omics technique enables investigation of disease at its earliest stages

How do you track down individual diseased cells in an intact brain or human heart? Searching is like finding a needle in a haystack. The teams of Ali Ertürk at Helmholtz Munich and LMU Munich together with Matthias Mann at the Max Planck Institute for Biochemistry in Martinsried near Munich have now developed a new technique called DISCO-MS to solve this problem. DISCO-MS uses robotics to acquire proteomic data from precisely identified “disease” cells early in disease.

Most illnesses are initially asymptomatic, and those affected often still feel well—symptoms have not yet appeared, or are still too mild to be aware of. However, something has changed inside the body: the virus may have started replicating, or the rogue cells may be dividing more often than they should. But how to perceive these changes?

Researchers face a similar dilemma when studying the early development of disease. Even when using animal models, scientists have rarely been able to pinpoint small sites of disease initiation or describe the exact molecular changes that drive disease progression.

This task has become easier with the development of DISCO-MS by Ertürk and Mann’s research team in Germany. DISCO-MS combines methods for clearing mouse and human tissues with the latest robotic and proteomic techniques to determine their molecular makeup.

DISCO-MS: Transparency in detecting early molecular changes

DISCO-MS starts with so-called DISCO tissue clearing, which makes mouse bodies or human organs transparent – making them easy to image. Therefore, fluorescently labeled cells can be easily identified in intact tissues or at specific sites using high-resolution 3D microscopy.

Once areas of interest are identified, they are isolated using a new robotic technology called DISCO-bot, developed by mechanical engineer Furkan Öztürk, a Ph.D. student in Ertürk’s laboratory. The robot-assisted extracted tissue was proteomically analyzed using an advanced mass spectrometry (MS) method developed by Andreas-David Brunner, a former Ph.D. student in Mann’s lab. This high-tech approach allows for complete molecular characterization of any desired tissue region identified in 3D throughout the mouse body or human organ.

early detection of disease

To demonstrate the power of the method, first author Harsharan Singh Bhatia and colleagues applied DISCO-MS to atherosclerotic plaques (pathologically hardened and narrowing of blood vessels). In tissue samples from AD models, the team applied artificial intelligence (AI) to identify plaques typical of AD early in the disease, which were difficult to detect by any other method. Subsequent proteomic analysis of plaques provided an unbiased and large-scale study of proteins affected by AD, revealing new molecular players that may serve as biomarkers for Alzheimer’s disease.

In the human heart, the researchers were interested in the composition of the tissue surrounding atherosclerotic plaques, which can be seen soon after the tissue has been cleared. AI detection and robotically extracted tissue again allowed the identification of dysregulated molecular pathways in human heart cells associated with aortic plaques. These results are key findings because they form the basis of potential therapeutic targets.

DISCO-MS is the first spatial omics technique for full 3D volumes, accelerating the study of complex diseases ranging from cancer to metabolic disorders. Because DISCO-MS is used with preclinical and clinical tissues, it enables research in the early stages of disease and the subsequent development of potential new treatments.

Papers published in journals cell.